Abstract 1280: Immunologic effect of PARP inhibitors as maintenance therapy in ovarian cancer patients
Authors: Junsik Park, Miran Lee, Yup Kim, Yoo-Na Kim, Yong-Jae Lee, Jung-Yun Lee
Journal: Cancer Research (2022)

Abstract Poly (adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) are becoming the standard of care for ovarian cancer. The greatest benefit has been observed in patients who have mutations in BRCA1/2 or related genes in the homologous recombination (HR) DNA repair pathway. Nonetheless, responses to PARPi were not durable, indicating that strategies to prevent recurrence and overcome resistance, such as combinations with immune checkpoint inhibitors (ICIs), are of high priority. However, most studies on PARPi have focused on the tumor itself and synthetic lethality. The immunological effect, particularly the effect on adaptive immune response, has been overlooked. PARP is expressed in almost all cells, and it regulates the transcription of various genes through poly(ADP-ribosyl)ation. Therefore, we hypothesized that PARPi affect the composition and functions of T cells in the maintenance therapy setting, and consequently reconstitute the anti-tumor immune response in ovarian cancer. Here, we collected serial peripheral blood mononuclear cells (PBMCs) from PARPi-treated patients and analyzed their dynamic immunologic changes using muticolor flow cytometry. The PBMCs were collected during PARPi maintenance therapy, and the time points included pre-treatment as well as 1 month and 3 months after the initiation of treatment. Olaparib or niraparib was used as maintenance therapy. First, the percentages of CD4, CD8, and FoxP3+regulatory T cells (Treg cells) were compared at each time point and by PARPi type. Interestingly, the proportion of Treg cells increased at 1 and 3 months after initiation, especially in the niraparib group. However, there were no significant changes in the proportion of CD4 and CD8 T cells. Second, we analyzed immune checkpoints and properties in each T cell population. We found that the PD-1 expression on Treg cells decreased after 1 and 3 months. Although the percentage of Treg cells increased, proliferative Ki-67+Treg cells decreased after 1 and 3 months, especially in the niraparib group. Third, intracellular staining assay was performed to measure functional changes of T cells during PARPi treatment. IFN-γ and/or TNF-α producing CD8 and CD4 T cells decreased after 1 month compared to pre-treatment. Finally, proliferative Ki-67+CD8 T cells and PD-1+CD8 T cells decreased after 72 hours of in vitro olaparib treatment compared to the control group. In conclusion, long-term PAPRi treatment may affect Treg cells and CD8 T cells. However, strategies to overcome negative effects of PARPi and their detailed mechanisms need to be further investigated. Additional data in this regard will be presented at the meeting. Citation Format: Junsik Park, Miran Lee, Yup Kim, Yoo-Na Kim, Yong-Jae Lee, Jung-Yun Lee. Immunologic effect of PARP inhibitors as maintenance therapy in ovarian cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1280.